The final analysis of the randomised phase II/III JCOG1008 trial confirmed the non-inferiority of weekly cisplatin + radiotherapy (RT) compared to a traditional three-weekly cisplatin schedule in combination with RT in post-operative patients with squamous cell carcinoma of the head and neck (SCCHN). Furthermore, data from the RADIO trial showed that this weekly schedule also comes with a lower rate of ototoxicity than the 3-weekly regimen.
JCOG1008 is a randomised phase II/III trial comparing cisplatin at a weekly (qw) dose of 40 mg/m2 to a three-weekly (q3w) dose of 100 mg/m2 both in combination with radiotherapy (RT, 66 Gy over 33 fractions) in post-operative, high-risk SCCHN patients.1 Previously, an interim analysis of this trial demonstrated non-inferiority of the weekly regimen in terms of overall survival (OS). During ESMO 2024, the final analysis of this trial was presented.1 In addition to this, a second study which was also presented at ESMO 2024 (RADIO) specifically compared the ototoxicity of the two regimens.2
JCOG1008 enrolled postoperative patients with pathological stage III/IV SCCHN with a microscopic positive margin and/or extranodal extension. Patients were randomly assigned to cisplatin 40 mg/m2/qw or 100 mg/m2/q3w both in combination with radiotherapy (RT, 66 Gy over 33 fractions). The primary objective of the phase III part of the study was to show non-inferiority in terms of overall survival (OS) for the weekly regimen as compared to the 3-weekly schedule. Secondary endpoints of JCOG1008 included relapse-free survival (RFS), local relapse-free survival (LRFS) and safety.
The study enrolled a total of 261 patients, with a median age of 62 years. Patients in the qw arm received a median of 6 treatment cycles as compared to 3 cycles in the q3w arm. The median cumulative dose of cisplatin was reported at 280 mg/m2 with 3-weekly dosing as compared to 236 mg/m2 in the qw arm, with a corresponding estimated dose intensity of 29.3 and 33.6 mg/m2, respectively.
The final analysis of the study, after a median follow-up of 5.6 years, confirmed the findings of the interim analysis, demonstrating non-inferiority of qw vs. q3w cisplatin dosing, with a 5-year OS of 58.7% with the q3w regimen as compared to 71.2% with the weekly dose (HR[95%CI]: 0.76[0.52-1.12], margin for non-inferiority: 1.32). The corresponding 5-year RFS rates in this final analysis were 53.0% and 64.3%, respectively (HR[95%CI]: 0.81[0.57-1.16]). Distant recurrences occurred in 34 patients treated with the 3-weekly regimen while this was only the case in 24 patients receiving the qw schedule. Five-year rates of locoregional recurrence were 57.2% with q3w cisplatin as compared to 68.8% with the weekly regimen.1
Regarding late adverse events, the 3-weekly regimen was associated with a 91.5% rate of any grade adverse events (AE), with 10.1% of grade ≥3 AEs. Among patients receiving weekly cisplatin, these rates were 94.2% and 13.2% respectively.1 Interestingly, final results of the RADIO trial which were also presented at ESMO 2024 showed that a weekly dose of 40 mg/m2 cisplatin came with a significantly lower incidence of grade ≥2 ototoxicity than the 3-weekly 100 mg/m2 dose.2 In this trial, grade ≥2 hearing impairment at one year was observed in 64.0% of patients treated with the 3-weekly dose as compared to 40.8% with the weekly regimen (HR[95%CI]: 0.39[0.17-0.87]; p= 0.027).2
The final analysis of JCOG1008 confirmed the non-inferior OS with weekly cisplatin + RT compared to q3w cisplatin +RT in post-operative SCCHN patients. Interestingly, data from the RADIO trial showed that this weekly schedule also comes with a lower rate of ototoxicity. As such, these findings provide further reassurance for the use of qw cisplatin in this setting.
References
1. Tahara M, et al. Final analysis of a phase II/III trial of post-operative chemoradiotherapy comparing 3-weekly cisplatin with weekly cisplatin in high-risk patients with squamous cell carcinoma of the head and neck (JCOG1008). Presented at ESMO 2024; Abstract 851MO.
2. Kuruvilla M, et al. Final results: Randomized assessment of cisplatin dosing interval for ototoxicity (RADIO) trial comparing chemoradiation (CRT) with cisplatin q3weekly to weekly for locally advanced squamous cell carcinoma of the head and neck (LASCCHN). Presented at ESMO 2024; Abstract LBA37.
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